Browsing by Subject "cytokines"

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  • Nordgreen, Janicke; Edwards, Sandra A.; Boyle, Laura Ann; Bolhuis, J. Elizabeth; Veit, Christina; Sayyari, Amin; Marin, Daniela E.; Dimitrov, Ivan; Janczak, Andrew M.; Valros, Anna (2020)
    Sickness can change our mood for the worse, leaving us sad, lethargic, grumpy and less socially inclined. This mood change is part of a set of behavioral symptoms called sickness behavior and has features in common with core symptoms of depression. Therefore, the physiological changes induced by immune activation, for example following infection, are in the spotlight for explaining mechanisms behind mental health challenges such as depression. While humans may take a day off and isolate themselves until they feel better, farm animals housed in groups have only limited possibilities for social withdrawal. We suggest that immune activation could be a major factor influencing social interactions in pigs, with outbreaks of damaging behavior such as tail biting as a possible result. The hypothesis presented here is that the effects of several known risk factors for tail biting are mediated by pro-inflammatory cytokines, proteins produced by the immune system, and their effect on neurotransmitter systems. We describe the background for and implications of this hypothesis.
  • Kakkola, L.; Denisova, O. V.; Tynell, J.; Viiliainen, J.; Ysenbaert, T.; Matos, R. C.; Nagaraj, A.; Öhman, Tiina; Kuivanen, S.; Paavilainen, H.; Feng, L.; Yadav, B.; Julkunen, I.; Vapalahti, O.; Hukkanen, V.; Stenman, J.; Aittokallio, T.; Verschuren, E. W.; Ojala, P. M.; Nyman, T.; Saelens, X.; Dzeyk, K.; Kainov, D. E. (2013)
  • Lohtaja, Milka (Helsingfors universitet, 2016)
    Chlamydia pneumoniae is an intracellular bacterium that causes a variety of respiratory infections to humans such as pneumonia and bronchitis. In addition C. pneumoniae -infection has been associated with multiple chronic diseases of which the most important are atherosclerosis and vascular diseases, asthma, chronic obstructive pulmonary disease and different kinds of neurological disorders. C. pneumoniae is a very common pathogen that has the ability to hide in the system in a persistent chronic form out of reach of the immune defences. C. pneumoniae has been shown to infect many other cell types besides bronchial epithelial cells. These cells include monocytes, macrophages and vascular endothelial cells. C. pneumoniae induces the secretion of different kinds of cytokines and cell signalling molecules and the expression of adhesion molecules in all of these cell types. Too strong cytokine and immune response is detrimental to cells and to whole system. Currently available antibiotics aren't effective enough against C. pneumoniae -infection, especially against its chronic form. Furthermore, the lack of effective anti-chlamydial drugs impairs the research of the association between C. pneumoniae and chronic diseases. The aim of this study was to investigate the effect of anti-chlamydial compounds on the release of cytokines and cell signaling molecule, nitric oxide, induced by C. pneumoniae -infection in different cell types. These anti-chlamydial compounds are currently under the investigation in the faculty of pharmacy. In addition the anti-inflammatory properties of the compounds were further investigated with the help of lipopolysaccharide of another gram-negative bacterium E. coli. The groups of compounds investigated in this study were β2,2-amino acid derivatives, Schisandra chinensis -lignans, TE-compounds synthesized in Vienna and benzimidazole compounds synthesized in the faculty of pharmacy. There were four cell types used in this study, HL- and BEAS-2B-epithelial cells, THP-1-monocytes/macrophages and RAW264.7-macrophages. The study focused on the determination of vascular endothelial growth factor VEGF and interleukins IL-8, IL-10 and IL-12. The concentrations of cytokines in the cell medium were measured after infection using ELISA-method. Nitric oxide measurements were also determined from the medium using Griess' reagent. Immunofluorescence labeling was used to confirm the infection and the infection was verified by fluorescence microscope. In addition some of the compounds were tested for the cell viability using resazurin assay. All the groups of compounds showed desired effects on the release of cytokines and nitric oxide. Especially β2,2-amino acid derivatives reduced clearly the release of both cytokines and nitric oxide. β2,2-amino acid derivatives could thus be potential drug candidates for the development of anti-chlamydial and anti-inflammatory drugs. Schisandra chinensis -lignans inhibited especially the release of nitric oxide in both C. pneumoniae -infected and LPS-stimulated cells which may tell about their broad anti-inflammatory properties. There were also found desired results with TE-compounds and benzimidazole compounds. Interleukins were not secreted by any of the studied cells so that part needs more research and further investigation. Based on the results found in this study it can be concluded that the studied compounds could be potential lead compounds in the discovery of anti-chlamydial drugs and drugs that specifically inhibit C. pneumoniae -infection. Further research is needed concerning the effects of these compounds on cytokines and especially on chronic infection.
  • Loo, Evelyn Xiu Ling; Ooi, Delicia Shu Qin; Ong, Minyee; Ta, Le Duc Huy; Lau, Hui Xing; Tay, Michelle Jia Yu; Yap, Qai Ven; Chan, Yiong Huak; Tham, Elizabeth Huiwen; Goh, Anne Eng Neo; Van Bever, Hugo; Teoh, Oon Hoe; Eriksson, Johan Gunnar; Chong, Yap Seng; Gluckman, Peter; Yap, Fabian Kok Peng; Karnani, Neerja; Xu, Jia; Tan, Karen Mei Ling; Tan, Kok Hian; Lee, Bee Wah; Kramer, Michael; Shek, Lynette Pei-Chi; Meaney, Michael J.; Broekman, Birit F. P. (2022)
    Background: Epidemiological studies suggest a link between eczema and attention deficit hyperactivity disorder (ADHD), but underlying mechanisms have not been examined.Objective: We aim to investigate the association between eczema and subsequent ADHD symptoms in the Growing Up in Singapore Towards healthy Outcomes cohort and explore the role of pro-inflammatory cytokines and gut microbiome.Methods: The modified International Study of Asthma and Allergies in Childhood questionnaire and Computerized Diagnostic Interview Schedule for Children Version IV were administered to assess reported eczema within the first 18 months and presence of ADHD symptoms at 54 months, respectively. Skin prick testing at 18 months, cytokines in maternal blood during pregnancy and cord blood and the mediating role of the gut microbiome at 24 months were assessed.Results: After adjusting for confounders, eczema with or without a positive skin prick test was associated with doubling the risk of ADHD symptoms. No differences in maternal and cord blood cytokines were observed in children with and without eczema, or children with and without ADHD. Gut microbiome dysbiosis was observed in children with eczema and children with ADHD. Children with eczema also had lower gut bacterial Shannon diversity. However, the relationship between eczema and ADHD was not mediated by gut microbiome.Conclusion: Early life eczema diagnosis is associated with a higher risk of subsequent ADHD symptoms in children. We found no evidence for underlying inflammatory mechanism or mediation by gut microbiome dysbiosis. Further research should evaluate other mechanisms underlying the link between eczema and ADHD.
  • Niinistö, Sari; Miettinen, Maija E.; Cuthbertson, David; Honkanen, Jarno; Hakola, Leena; Autio, Reija; Erlund, Iris; Arohonka, Petra; Vuorela, Arja; Härkönen, Taina; Hyöty, Heikki; Krischer, Jeffrey P.; Vaarala, Outi; Knip, Mikael; Virtanen, Suvi M. (2022)
    AimsAltered immune functions as well as fatty acid intake and status have been associated with the development of type 1 diabetes. We aimed to study the relationship between fatty acids and immunological markers in young children with increased genetic risk for type 1 diabetes in order to define putative mechanisms related to development of islet autoimmunity. MethodsSerum samples for fatty acid and immunological marker measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children born between 2002 and 2007 in 15 countries. Case children (n = 95) were defined as having repeated positivity for at least two out of four diabetes-associated autoantibodies. For each case child, control children were selected matched for country and date of birth (n = 173). Serum fatty acids and immunological markers were measured from cord serum and at the age of 6 and 12 months. Spearman correlation coefficients were calculated between fatty acids and immunological markers. ResultsCorrelations between circulating fatty acids and immunological markers were different in case children who developed islet autoimmunity than in control children already at birth continuing across the first year of life. In case children, saturated fatty acids (SFAs) showed stronger correlations with immunological markers, while in controls, polyunsaturated fatty acids (PUFAs) showed stronger correlations. ConclusionsIn cases, SFAs were associated with several immunological markers (CXCL10, IL-6, IL-9, IL-17, and CM-CSF) previously linked to the type 1 diabetes disease process. Findings indicate that fatty acids could have immunomodulatory potential in the early phase of the disease development, although causality between fatty acids and the immunological pathways remains to be explored. Trial registry numberNCT00179777
  • Wang, Qin; Wurtz, Peter; Auro, Kirsi; Morin-Papunen, Laure; Kangas, Antti J.; Soininen, Pasi; Tiainen, Mika; Tynkkynen, Tuulia; Joensuu, Anni; Havulinna, Aki S.; Aalto, Kristiina; Salmi, Marko; Blankenberg, Stefan; Zeller, Tanja; Viikari, Jorma; Kahonen, Mika; Lehtimaki, Terho; Salomaa, Veikko; Jalkanen, Sirpa; Jarvelin, Marjo-Riitta; Perola, Markus; Raitakari, Olli T.; Lawlor, Debbie A.; Kettunen, Johannes; Ala-Korpela, Mika (2016)
    Background: Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood. Methods: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24-49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception. Results: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery. Conclusions: Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation.
  • Katila, Terttu; Ferreira-Dias, Graca (2022)
    Simple Summary Our understanding about inflammation of the endometrium after mating and susceptibility of mares to endometritis has changed in the last 100 years since it was recognized for the first time. Initially, it was believed that bacteria introduced into the uterus during mating could infect the uterus until it was shown that sperm induce neutrophilia. It was realized that post breeding endometritis (PBE) is a physiological defense mechanism used to clean the uterus from excess semen and inflammatory by-products. In mares susceptible to endometritis, PBE can be prolonged beyond the normal duration of 24 h. Delayed uterine clearance due to conformational defects, deficient myometrial contractions, and failure of the cervix to relax is detected by intrauterine fluid accumulation and is an important reason for susceptibility to endometritis. Untreated prolonged PBE can lead to bacterial or fungal endometritis called persistent or chronic endometritis. Multiparous aged mares are more likely to be susceptible. When sperm arrive in the uterus, pro-inflammatory cytokines are released. They attract neutrophils and induce modulatory cytokines which control inflammation. However, persistence of neutrophils and pro-fibrotic cytokines can have deleterious effects in inducing endometrosis. In this paper, the pathogenesis of fibrosis is reviewed. Endometritis and endometrosis are interconnected influencing each other. In this paper, the evolution of our understanding about post breeding endometritis (PBE), the susceptibility of mares, and events leading to endometrosis are reviewed. When sperm arrive in the uterus, pro-inflammatory cytokines and chemokines are released. They attract neutrophils and induce modulatory cytokines which control inflammation. In susceptible mares, this physiological defense can be prolonged since the pattern of cytokine release differs from that of resistant mares being delayed and weaker for anti-inflammatory cytokines. Delayed uterine clearance due to conformational defects, deficient myometrial contractions, and failure of the cervix to relax is detected by intrauterine fluid accumulation and is an important reason for susceptibility to endometritis. Multiparous aged mares are more likely to be susceptible. Untreated prolonged PBE can lead to bacterial or fungal endometritis called persistent or chronic endometritis. Exuberant or prolonged neutrophilia and cytokine release can have deleterious and permanent effects in inducing endometrosis. Interactions of neutrophils, cytokines, and prostaglandins in the formation of collagen and extracellular matrix in the pathogenesis of fibrosis are discussed. Endometritis and endometrosis are interconnected, influencing each other. It is suggested that they represent epigenetic changes induced by age and hostile uterine environment.
  • Kaivola, Juha; Nyman, Tuula Anneli; Matikainen, Sampsa (2021)
    SARS-CoV-2 is a new type of coronavirus that has caused worldwide pandemic. The disease induced by SARS-CoV-2 is called COVID-19. A majority of people with COVID-19 have relatively mild respiratory symptoms. However, a small percentage of COVID-19 patients develop a severe disease where multiple organs are affected. These severe forms of SARS-CoV-2 infections are associated with excessive production of pro-inflammatory cytokines, so called "cytokine storm". Inflammasomes, which are protein complexes of the innate immune system orchestrate development of local and systemic inflammation during virus infection. Recent data suggest involvement of inflammasomes in severe COVID-19. Activation of inflammasome exerts two major effects: it activates caspase-1-mediated processing and secretion of pro-inflammatory cytokines IL-1 beta and IL-18, and induces inflammatory cell death, pyroptosis, via protein called gasdermin D. Here, we provide comprehensive review of current understanding of the activation and possible functions of different inflammasome structures during SARS-CoV-2 infection and compare that to response caused by influenza A virus. We also discuss how novel SARS-CoV-2 mRNA vaccines activate innate immune response, which is a prerequisite for the activation of protective adaptive immune response.
  • Alamo, Maria Montserrat Rivera del; Reilas, Tiina; Lukasik, Karolina; Galvão, Antonio; Yeste, Marc; Katila, Terttu (2021)
    Simple Summary While intrauterine devices (IUDs) are used to prevent disturbing oestrous behaviour in sport mares, their mechanism of action has not been elucidated. The presence of an embryo or an IUD prevents cyclooxygenase-2 (COX-2) and subsequently prostaglandin (PG) release and luteolysis. It has been suggested that a plastic sphere would mimic the embryo by mechanotransduction. However, there is some evidence that IUDs also cause endometrial inflammation, which might contribute to luteostasis. The aim of this study was to investigate the presence and time course of possible inflammation by evaluating changes in uterine fluid composition. On Day 10 after ovulation, events leading to COX-2 and prostaglandin F-2 alpha (PGF(2 alpha)) inhibition start, whereas either luteolysis occurs or the corpus luteum is maintained on Day 15. Therefore, uterine lavage fluid was evaluated at two time points in inseminated mares, either pregnant or not, and in mares inserted with an IUD. On Day 10, PGF(2 alpha) concentration in the fluid was significantly lower in the IUD group than in the pregnant mare one but did not differ from the non-pregnant mare group. On Day 15, the IUD group had significantly higher levels of the modulatory cytokine IL-10 and inhibin A, which could indicate previous inflammation and resolution stage. Intrauterine devices (IUDs) are used in mares to suppress oestrous behaviour, but the underlying mechanism is yet to be elucidated. The presence of an embryo or an IUD prevents cyclooxygenase-2 (COX-2) and, subsequently, prostaglandin (PG) release and luteolysis. However, inflammation may also be involved. Endometrial inflammatory markers in uterine lavage fluid were measured on Day 10 (EXP 1, n = 25) and Day 15 (EXP 2, n = 27) after ovulation in inseminated mares, non-pregnant or pregnant, and in mares in which a small plastic sphere had been inserted into the uterus 4 (EXP 1) or 3 days (EXP 2) after ovulation. Uterine lavage fluid samples were analysed for nitric oxide (NO), prostaglandin E-2 (PGE(2)) (only EXP 1), prostaglandin F-2 alpha (PGF(2 alpha)), inhibin A and cytokines, and blood samples for progesterone and oestradiol. On Day 10, the concentration of PGF(2 alpha) was lower (p < 0.05) in the IUD group than in pregnant mares. The concentration of the modulatory cytokine IL-10 was significantly higher in the IUD group in comparison to non-pregnant mares, and inhibin A was significantly higher in IUD mares than in the pregnant counterparts on Day 15. The results suggest that the presence of IUD causes endometrial inflammation which is at a resolution stage on Day 15.
  • Paaso, Anna; Koskimaa, Hanna-Mari; Welters, Marij J. P.; Kero, Katja; Rautava, Jaana; Syrjänen, Kari; van Der Burg, Sjoerd H.; Syrjänen, Stina (2021)
    Objectives: Natural history of human papillomavirus (HPV) infection in the head and neck region is poorly understood, and their impact on collective HPV-specific immunity is not known. Materials and methods: In this study, we have performed a systematic analysis of HPV16-specific cell-mediated immunity (CMI) in 21 women with known oral and genital HPV DNA status and HPV serology (Ab) based on 6-year follow-up data. These women being a subgroup from the Finnish Family HPV Study were recalled for blood sampling to be tested for their CMI-responses to HPV16 E2, E6, and E7 peptides. Results: The results showed that HPV16 E2-specific lymphocyte proliferation was more prevalent in women who tested HPV16 DNA negative in oral mucosa and were either HPV16 seropositive or negative than in HPV16 DNA+/Ab+ women (p = 0.046 and p = 0.035). In addition, the HPV16 DNA-/Ab- women most often displayed E6-specific proliferation (p = 0.020). Proportional cytokine profiles indicated that oral HPV16-negative women were characterized by prominent IFN-gamma and IL-5 secretion not found in women with persisting oral HPV16 (p = 0.014 and p = 0.040, respectively). Conclusions: Our results indicate that the naturally arising immune response induced by oral HPV infections displays a mixed Th1/Th2/Th17 cytokine profile while women with persisting oral HPV16 might have an impaired HPV16-specific CMI, shifted partly toward a Th2 profile, similarly as seen earlier among patients with high-grade genital HPV lesions. Thus, the lack of HPV 16 E2 and E6 specific T memory cells and Th2 cytokines might also predispose women for persistent oral HPV16 infection which might be related to the risk of cancer.
  • Gadina, Massimo; Le, Mimi T.; Schwartz, Daniella M.; Silvennoinen, Olli; Nakayamada, Shingo; Yamaoka, Kunihiro; O'Shea, John J. (2019)
    Cytokines are critical mediators of diverse immune and inflammatory diseases. Targeting cytokines and cytokine receptors with biologics has revolutionized the treatment of many of these diseases, but targeting intracellular signalling with Janus kinase (JAK) inhibitors (jakinibs) now represents a major new therapeutic advance. We are still in the first decade since these drugs were approved and there is still much to be learned about the mechanisms of action of these drugs and the practical use of these agents. Herein we will review cytokines that do, and just as importantly, do not signal by JAKs, as well as explain how this relates to both efficacy and side effects in various diseases. We will review new, next-generation selective jakinibs, as well as the prospects and challenges ahead in targeting JAKs.
  • Hose, Alexander J.; Depner, Martin; Illi, Sabina; Lau, Susanne; Keil, Thomas; Wahn, Ulrich; Fuchs, Oliver; Pfefferle, Petra Ina; Schmausser-Hechfellner, Elisabeth; Genuneit, Jon; Lauener, Roger; Karvonen, Anne M.; Roduit, Caroline; Dalphin, Jean-Charles; Riedler, Josef; Pekkanen, Juha; von Mutius, Erika; Ege, Markus J.; Bauer, Carl Peter; Forster, Johannes; Zepp, Fred; Wahn, Volker; Schuster, Antje; Bergmann, Renate L.; Bergmann, Karl E.; Reich, Andreas; Grabenhenrich, Linus; Schaub, Bianca; Loss, Georg J.; Renz, Harald; Kabesch, Michael; Roponen, Marjut; Hyvarinen, Anne; Tiittanen, Pekka; Remes, Sami; Braun-Fahrlander, Charlotte; Frei, Remo; Kaulek, Vincent; Dalphin, Marie-Laure; Doekes, Gert; Blumer, Nicole; Frey, Urs; MAS Study Grp; PASTURE Study Grp (2017)
    Background: Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. Objective: We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Methods: Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. Results: The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-gamma ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. Conclusions: LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function.
  • Wang, Jun; Conti, David; Epeldegui, Marta; Ollikainen, Miina; Tyndale, Rachel F.; Hwang, Amie Eunah; Magpantay, Larry; Mack, Thomas McCulloch; Martinez-Maza, Otoniel; Kaprio, Jaakko; Cozen, Wendy (2021)
    Simple Summary: Smoking is associated with a moderate increased risk of Hodgkin and follicular lymphoma. To help understand why, we examined lymphoma-related biomarker levels among 134 smoking and non-smoking twins (67 pairs) ascertained from the Finnish Twin Cohort. We validated self-reported smoking history by measuring serum cotinine, a metabolite of nicotine, from previously collected frozen serum samples. In total, 27 immune biomarkers were assayed using the Luminex Multiplex platform (R & D Systems). We found that four immune response biomarkers were higher and one was lower among smoking compared to non-smoking twins. The strongest association was observed for CCL17/TARC, a biomarker elevated in Hodgkin lymphoma patients. Immune biomarker levels were similar in former smokers and non-smokers. Current smoking may increase levels of immune proteins that could partially explain the association between smoking and risk of certain lymphomas.Smoking is associated with a moderate increased risk of Hodgkin and follicular lymphoma. To understand why, we examined lymphoma-related biomarker levels among 134 smoking and non-smoking twins (67 pairs) ascertained from the Finnish Twin Cohort. Previously collected frozen serum samples were tested for cotinine to validate self-reported smoking history. In total, 27 immune biomarkers were assayed using the Luminex Multiplex platform (R & D Systems). Current and non-current smokers were defined by a serum cotinine concentration of > 3.08 ng/mL and & LE;3.08 ng/mL, respectively. Associations between biomarkers and smoking were assessed using linear mixed models to estimate beta coefficients and standard errors, adjusting for age, sex and twin pair as a random effect. There were 55 never smokers, 43 current smokers and 36 former smokers. CCL17/TARC, sgp130, haptoglobin, B-cell activating factor (BAFF) and monocyte chemoattractant protein-1 (MCP1) were significantly (p < 0.05) associated with current smoking and correlated with increasing cotinine concentrations (P-trend < 0.05). The strongest association was observed for CCL17/TARC (P-trend = 0.0001). Immune biomarker levels were similar in former and never smokers. Current smoking is associated with increased levels of lymphoma-associated biomarkers, suggesting a possible mechanism for the link between smoking and risk of these two B-cell lymphomas.
  • Gebraad, Arjen; Kornilov, Roman; Kaur, Sippy; Miettinen, Susanna; Haimi, Suvi; Peltoniemi, Hilkka; Mannerström, Bettina; Seppänen-Kaijansinkko, Riitta (2018)
    Intercellular communication is essential in bone remodelling to ensure that new bone is formed with only temporary bone loss. Monocytes (MCs) and osteoclasts actively take part in controlling bone remodelling by providing signals that promote osteogenic differentiation of mesenchymal stem/stromal cells (MSCs). Extracellular vesicles (EVs) have attracted attention as regulators of bone remodelling. EVs facilitate intercellular communication by transferring a complex cargo of biologically active molecules to target cells. In the present study, we evaluated the potency of EVs from MCs and osteoclasts to induce a lineage-specific response in MSCs. We analysed gene expression and protein secretion by both adipose tissue-derived MSCs and bone marrow-derived MSCs after stimulation with EVs from lipopolysaccharide-activated primary human MCs and (mineral-resorbing) osteoclasts. Isolated EVs were enriched in exosomes (EVs of endosomal origin) and were free of cell debris. MC- and osteoclast-derived EVs were taken up by adipose tissue-derived MSCs. EVs from activated MCs promoted the secretion of cytokines by MSCs, which may represent an immunomodulatory mechanism. MC-derived EVs also upregulated the expression of genes encoding for matrix metalloproteinases. Therefore, we hypothesize that MCs facilitate tissue remodelling through EV-mediated signalling. We did not observe a significant effect of osteoclast-derived EVs on gene expression or protein secretion in MSCs. EV-mediated signalling might represent an additional mode of cell-cell signalling during the transition from injury and inflammation to bone regeneration and play an important role in the coupling between bone resorption and bone formation. DatabaseGene expression data are available in the GEO database under the accession number .
  • Liimatainen, Sanna (Helsingin yliopisto, 2020)
    Parodontiitti ja diabetes ovat kroonisia, monitekijäisiä sairauksia, joiden kaksisuuntainen yhteys on ollut runsaan tutkimuksen kohteena. Molemmat ovat yleisiä, alidiagnosoituja sairauksia Suomen väestössä. Tämän kirjallisuuskatsauksena toteutettavan tutkielman tavoitteena on tarkastella parodontiitin ja diabeteksen patofysiologisia vuorovaikutusmekanismeja ja parodontologisen hoidon merkitystä diabeteksessa sekä arvioida näiden kliinistä merkitystä diabetespotilaita hoitavan lääkärin ja hammaslääkärin työssä. Tutkielmaa varten on perehdytty aiheeseen liittyviin tutkimuksiin ja kirjallisuuteen. Tutkimusten perusteella diabetespotilaat ovat suuremmassa riskissä sairastua parodontiittiin ja kiinnityskudostuho on heillä vaikea-asteisempaa. Diabeteksesta johtuvat hyperglykemia ja lipidimetabolian muutokset kiihdyttävät tulehdusta parodontaalikudoksissa muun muassa lisäämällä paikallisia proinflammatorisia sytokiineja, reaktiivisia happijohdannaisia, AGE/RAGE interaktioita ja RANKL/osteoprotegeriinin aktivaatiota. Parodontiitin aiheuttama systeeminen tulehduskuorma voi heikentää diabetespotilaan verensokeritasapainoa ja lisätä riskiä diabetekseen liittyviin komplikaatioihin. Diabetesta sairastamattomilla parodontiitti lisää riskiä sairastua prediabetekseen ja tyypin 2 diabetekseen. Parodontologisella hoidolla saattaa olla suotuisia vaikutuksia sokerihemoglobiinin ja lipidiprofiiliin tyypin 2 diabetesta sairastavilla. Diabetespotilaan suun terveys vaatii erityishuomiota hammaslääkäreiltä ja lääkäreiltä. Diabeteksen huono hoitotasapaino korreloi merkittävästi iensairauksien ongelmiin. Hoitamaton parodontiitti puolestaan voi suurentaa veren glukoosipitoisuutta.
  • Saarinen, Aino; Keltikangas-Jarvinen, Liisa; Dobewall, Henrik; Ahola-Olli, Ari; Salmi, Marko; Lehtimäki, Terho; Raitakari, Olli; Jalkanen, Sirpa; Hintsanen, Mirka (2021)
    Background: Previously, compassion has been found to protect against depressive symptoms, while emotional adversities in childhood are suggested to increase inflammatory responses. The current study investigated (a) whether emotional family environment in childhood predicts levels of such cytokines in adulthood that are previously found to be elevated in depression (interleukin [IL]-2, IL-6, IL-1b, monocyte chemoattractant protein-1, interferon-gamma [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]) and (b) whether these associations are modified by compassion in adulthood. Methods: The participants (N = 1,198-1,523) came from the prospective population-based Young Finns data. Emotional family environment and parental socioeconomic factors were evaluated in 1980; participants' compassion in 2001; and participants' cytokine levels and adulthood covariates in 2007. Results: Risky emotional family environment in childhood predicted higher levels of IL-2, IL-6, IFN-gamma, and TNF-alpha in adulthood. Additionally, there were significant interaction effects between compassion and emotional risk in childhood, when predicting IL-2, IL-6, and TNF-alpha. Specifically, individuals who grew up in a risky emotional family environment had on average higher levels of IL-2, IL-6, and TNF-alpha in adulthood when combined with low compassion. Conclusions: In individuals coming from risky emotional family environments, high compassion for others may protect against elevated levels of cytokines previously linked with depression.
  • Ziemele, Inga; Xu, Man; Vilmane, Anda; Rasa-Dzelzkaleja, Santa; Hedman, Klaus; Söderlund-Venermo, Maria; Gardovska, Dace; Nora-Krukld, Zaiga; Murovska, Modra (2019)
  • Veit, Christina; Janczak, Andrew M.; Ranheim, Birgit; Vas, Judit; Valros, Anna; Sandercock, Dale A.; Piepponen, Petteri; Dulgheriu, Daniela; Nordgreen, Janicke (2021)
    Poor health is a risk factor for damaging behaviors, but the mechanisms behind this link are unknown. Injection of pigs with lipopolysaccharide (LPS) can be used to model aspects of poor health. Recent studies have shown that LPS-injected pigs perform more tail- and ear-directed behavior compared to saline-injected pigs and suggest that pro-inflammatory cytokines may play a role in these behaviors. The aims of this study were to test the effect of LPS on the social behavior of pigs and the neurotransmitters and modulators in their brains and to test the effect of a nonsteroidal anti-inflammatory drug on the effects of LPS. Fifty-two female pigs (11-12 weeks) were allocated to four treatments comprising two injections: saline-saline (SS), saline-LPS (SL), ketoprofen-saline (KS), and ketoprofen-LPS (KL). Activity was scan-sampled every 5 min for 6 h after the last injection in the pen. Social behavior was observed continuously in 10 x 15-min bouts between 8 a.m. and 5 p.m. 1 day before (baseline) and 1 and 2 days after the injection. Saliva was analyzed for cortisol and plasma for tryptophan and kynurenine. The frontal cortex, hippocampus, hypothalamus, and brain stem were sampled 72 h after the injection and analyzed for cytokines and monoamines. LPS activated the HPA axis and decreased the activity within 6 h after the injection. Ketoprofen lowered the effect of LPS on cortisol release and attenuated the behavioral signs of sickness in challenged pigs. SL pigs manipulated the ears of their pen mates significantly longer than SS pigs 2 days after the injection. LPS had no observed effect on IFN-gamma, TNF-alpha, and IL-18. At 72 h after the injection, plasma tryptophan was depleted in SL pigs, and tryptophan and kynurenine concentrations in the frontal cortex and brain stem of SL pigs were significantly lower compared to those in SS pigs. Dopamine concentrations in the hypothalamus of SL pigs were significantly lower compared to those in SS pigs. Serotonin concentrations in the hypothalamus and noradrenaline concentrations in the hippocampus of SL pigs were significantly lower compared to those in KL pigs. In conclusion, LPS influenced the different neurotransmitters and modulators in the brain that are hypothesized to play an important role in the regulation of mood and behavior.
  • Rasheed, Kashif; Moens, Ugo; Policastro, Benedetta; Johnsen, John Inge; Koljonen, Virve; Sihto, Harri; Lui, Weng-Onn; Sveinbjørnsson, Baldur (2022)
    Merkel cell polyomavirus (MCPyV) is a causal factor in Merkel cell carcinoma (MCC). The oncogenic potential is mediated through its viral oncoproteins large T-antigen (LT) and small T-antigen (sT). Cytokines produced by tumor cells play an important role in cancer pathogenesis, and viruses affect their expression. Therefore, we compared human cytokine and receptor transcript levels in virus positive (V+) and virus negative (V−) MCC cell lines. Increased expression of IL-33, a potent modulator of tumor microenvironment, was observed in V+ MCC cell lines when compared to V− MCC-13 cells. Transient transfection studies with luciferase reporter plasmids demonstrated that LT and sT stimulated IL-33, ST2/IL1RL1 and IL1RAcP promoter activity. The induction of IL-33 expression was confirmed by transfecting MCC-13 cells with MCPyV LT. Furthermore, recombinant human cytokine domain IL-33 induced activation of MAP kinase and NF-κB pathways, which could be blocked by a ST2 receptor antibody. Immunohistochemical analysis demonstrated a significantly stronger IL-33, ST2, and IL1RAcP expression in MCC tissues compared to normal skin. Of interest, significantly higher IL-33 and IL1RAcP protein levels were observed in MCC patient plasma compared to plasma from healthy controls. Previous studies have demonstrated the implication of the IL-33/STL2 pathway in cancer. Because our results revealed a T-antigens-dependent induction of the IL-33/ST2 axis, IL-33/ST2 may play a role in the tumorigenesis of MCPyV-positive MCC. Therefore, neutralizing the IL-33/ST2 axis may present a novel therapeutic approach for MCC patients.
  • Palmroth, Maaria; Kuuliala, Krista; Peltomaa, Ritva; Virtanen, Anniina; Kuuliala, Antti; Kurttila, Antti; Kinnunen, Anna; Leirisalo-Repo, Marjatta; Silvennoinen, Olli; Isomäki, Pia (2021)
    Objective Current knowledge on the actions of tofacitinib on cytokine signaling pathways in rheumatoid arthritis (RA) is based on in vitro studies. Our study is the first to examine the effects of tofacitinib treatment on Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathways in vivo in patients with RA. Methods Sixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of constitutive and cytokine-induced phosphorylated STATs in peripheral blood monocytes, T cells and B cells were measured by flow cytometry at baseline and three-month visits. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response was also investigated. Results Tofacitinib, in csDMARDs background, decreased median disease activity score (DAS28) from 4.4 to 2.6 (p < 0.001). Tofacitinib treatment significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. However, the magnitude of the inhibitory effect depended on the cytokine and cell type studied, varying from 10% to 73% inhibition following 3-month treatment with tofacitinib. In general, strongest inhibition by tofacitinib was observed with STAT phosphorylations induced by cytokines signaling through the common-gamma-chain cytokine receptor in T cells, while lowest inhibition was demonstrated for IL-10 -induced STAT3 phosphorylation in monocytes. Constitutive STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was also downregulated by tofacitinib. Tofacitinib treatment downregulated the expression of several JAK-STAT pathway components in PBMCs, SOCSs showing the strongest downregulation. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response. Conclusions Tofacitinib suppresses multiple JAK-STAT pathways in cytokine and cell population specific manner in RA patients in vivo. Besides directly inhibiting JAK activation, tofacitinib downregulates the expression of JAK-STAT pathway components. This may modulate the effects of tofacitinib on JAK-STAT pathway activation in vivo and explain some of the differential findings between the current study and previous in vitro studies. Finally, baseline immunological markers associate with the treatment response to tofacitinib.